Effect of Vitamin D<sub>3</sub> and Omega-3 Fatty Acid Supplementation on Risk of Frailty
Authors: Ariela R. Orkaby, Rimma Dushkes, Rachel Ward, Luc Djousse, Julie E. Buring, I-Min Lee, Nancy R. Cook, Meryl S. LeBoff, Olivia I. Okereke, Trisha Copeland, JoAnn E. Manson
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Preventive strategies for frailty are needed. Whether supplements with anti-inflammatory properties, such as vitamin D<sub>3</sub>or marine omega-3 fatty acids, are useful for frailty prevention is unknown. <h3>Objective</h3> To test the effects of vitamin D<sub>3</sub>and omega-3 supplements on change in frailty in older individuals. <h3>Design, Setting, and Participants</h3> This study was conducted in 2021, as a prespecified ancillary to the Vitamin D and Omega-3 (VITAL) trial, a 2 × 2 factorial randomized clinical trial. A total of 25 871 individuals (men aged ≥50 years and women aged ≥55 years), without cancer or cardiovascular disease and with data on frailty, were recruited across all 50 US states from November 2011 to March 2014 and followed up through December 31, 2017. Data analysis for the ancillary study was conducted from December 1, 2019, to March 30, 2022. <h3>Interventions</h3> Vitamin D<sub>3</sub>, 2000 IU/d, and marine omega-3 fatty acids, 1 g/d. <h3>Main Outcomes and Measures</h3> Frailty was measured using a validated 36-item frailty index that includes measures of function, cognition, mood, and comorbidities from annual questionnaires. Change in frailty score from baseline to year 5, according to randomization, using an intention-to-treat protocol, was assessed using repeated measures. Cox proportional hazards regression models assessed incident frailty. In subgroup analysis, an alternative frailty definition, the physical phenotype, was used as a sensitivity analysis. <h3>Results</h3> Of 25 871 VITAL trial participants randomized, 25 057 had sufficient data to calculate a frailty index. Baseline mean (SD) age was 67.2 (7.0) years, and 12 698 (50.7.%) were women. Mean (SD) frailty score was 0.109 (0.090) (range, 0.00-0.685), and 3174 individuals (12.7%) were frail. During a median 5-year follow-up, mean (SD) frailty scores increased to 0.121 (0.099) (range, 0.00-0.792). Neither vitamin D<sub>3</sub>nor omega-3 fatty acid supplementation affected mean frailty scores over time (mean difference at year 5: vitamin D<sub>3</sub>, −0.0002;<i>P</i> = .85; omega-3 fatty acid, −0.0001;<i>P</i> = .90) or rate of change in mean frailty score (interaction with time: vitamin D<sub>3</sub>;<i>P</i> = .98; omega-3 fatty acid;<i>P</i> = .13) Incident frailty remained similar over time (interaction with time: vitamin D<sub>3</sub>,<i>P</i> = .90; omega-3 fatty acid;<i>P</i> = .32). Results were unchanged using the frailty physical phenotype. <h3>Conclusions and Relevance</h3> In this ancillary study of the VITAL randomized clinical trial, treatment with vitamin D<sub>3</sub>or omega-3 fatty acid supplementation, compared with placebo, did not affect the rate of frailty change or incidence over time. These results do not support routine use of either vitamin D<sub>3</sub>or omega-3 fatty acid supplementation for frailty prevention in generally healthy community-dwelling older adults not selected for vitamin D<sub>3</sub>deficiency. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01169259